Visual dysfunction is a common and frequently irreversible cause of disability in multiple sclerosis (MS). The anterior visual pathways, including the optic nerves, retina, chiasm, and tracts, are frequent sites for inflammation and demyelization, and axonal neuronal degeneration within these structures is a final common pathway to permanent visual loss. Recognized by MS experts as a critical dimension for clinical trial outcomes assessment, vision has been an important area of study that has resulted in identification of low-contrast letter acuity as a new measure. Low-contrast letter acuity detects even subtle visual impairment not captured by high-contrast visual acuity (VA) and demonstrated treatment effects in two recent phase 3 trials. Non-invasive ocular imaging, including optical coherence tomography (OCT) and scanning laser polarimetry with variable corneal compensation (GDx), has also become increasingly recognized in MS as a potential marker for axonal and neuronal loss. Retinal nerve fiber layer (RNFL) thinning and reductions in total macular volume correlate with reductions in low-contrast acuity at a single time point, and preliminary data suggest that RNFL axonal loss over time is associated with worsening visual function, even in the absence of acute optic neuritis (ON). These unique structure-function correlations make the anterior visual pathways an attractive model for examining therapeutic efficacy in MS clinical trials, particularly for the anticipated next generation of trials that will involve neuroprotective agents. While our cross-sectional, preliminary longitudinal, and clinical trial data represent a significant step toward refining and validating visual and ocular imaging outcomes for MS and ON, important questions remain that can only be addressed by large-scale collaborative studies of uniformly studied, heterogeneous MS cohorts and of patients with acute ON. This proposal will use the anterior visual pathways as a model for examining correlations of structure and function (vision and quality of life) in MS: Aim 1: Refine and validate low-contrast letter acuity, RNFL thickness by OCT (OCT-3 and ultra-high resolution) and GDx, and total macular volume by OCT as potential measures for clinical trials in MS. Aim 2: Using acute optic neuritis (ON) as a specific model, examine the timing of changes in RNFL thickness and macular volume, and define how OCT and GDx measures may provide insight into patterns across retinal quadrants and relative timing of axonal, neuronal, and functional loss for an MS lesion. Aim 3: Determine how low-contrast letter acuity, RNFL thickness, and total macular volume impact vision specific and overall health-related quality of life (HRQOL) in longitudinal studies of MS and ON.